Impaired behavioral inhibition in Fmr1 KO mice is linked to disrupted visual cortex theta oscillations

Fragile X syndrome (FX) is associated with sensory processing and learning deficits. Visual familiarity evokes persistent theta oscillations during passive stimulus presentation in the primary visual cortex (V1) and the hippocampus (HPC), which are impaired in V1 of FX. How does this activity change during active behavior? To address this, we performed Neuropixels recordings in V1, HPC, and the prefrontal cortex (PFC) during Go/No-Go visual discrimination behavior. Theta oscillations are reduced in FX in both V1 and HPC and are abolished during No-Go trials, correlating with excessive, incorrect licking behavior. In wild-type (WT) mice, V1 theta power strongly correlates with correct behavioral outcomes. PFC shows significantly reduced cue-related responses in FX. Together, these findings show loss of behavioral inhibition in FX correlated with attenuated theta activity in V1 and HPC and deficient top-down control from PFC. This work sheds light on circuit-level impairments underlying behavioral deficits in FX for potential therapeutic interventions.